ABSTRACT
To study the contribution of QRS prolongation to transplant‐free survival, we conducted an observational study of 68 patients with sarcoidosis‐related pulmonary hypertension. Every 10‐ms increase in QRS interval was associated with an adjusted HR of 1.23 (95% CI: 1.06, 1.44) for the composite outcome of lung transplantation and all‐cause mortality.
Keywords: electrocardiography, pulmonary sarcoidosis, risk stratification
1. Introduction
Sarcoidosis‐related pulmonary hypertension (SaPH) affects 5%–20% of patients with sarcoidosis and is a major cause of mortality, attributing to 31% of deaths [1, 2]. Classified by the World Symposium on Pulmonary Hypertension as Group 5 PH, SaPH can be caused by pulmonary vascular inflammation, pulmonary artery compression by mediastinal lymph nodes, left ventricular (LV) dysfunction, interstitial lung disease, and/or venous thromboembolic disease [1, 3]. LV dysfunction occurs clinically in 5%–10% of patients with sarcoidosis although studies combining imaging and autopsies have revealed cardiac disease in 20%–70% [4]. A noninvasive screening for cardiac sarcoidosis includes electrocardiography (ECG) to detect conduction abnormalities [3], where bundle branch blocks are observed in 12%–61% of patients [5]. While ECG abnormalities are associated with cardiovascular events and a trend toward increased mortality in sarcoidosis [6], its role in SaPH remains unclear. In this study, using a single‐center cohort, we characterized conduction abnormalities, specifically QRS prolongation, and its contribution to a composite outcome of lung transplantation and all‐cause mortality in SaPH. We hypothesized that QRS prolongation on ECG was associated with poor clinical outcomes and may help to prognosticate patients with SaPH.
2. Methods
This was a retrospective, observational single‐center study of patients with SaPH from January 1, 2010, to January 1, 2020. The study was deemed exempt by the Institutional Review Board at Boston University Medical Campus. Sarcoidosis was defined by both physician diagnosis and confirmatory tissue biopsy revealing non‐necrotizing/non‐caseating granulomas. PH was determined on right heart catheterization (RHC) by a mean pulmonary artery pressure (mPAP) > 20 mm Hg and further subclassified based on cardiopulmonary hemodynamics [7]. QRS prolongation was defined by a QRS interval ≥ 120 ms. We excluded patients with paced rhythms. Data collected included the following: (1) Demographics; (2) PH classification; (3) Comorbid conditions; (4) Sarcoidosis stage; (5) Pulmonary function testing; (6) Brain natriuretic peptide levels; (7) Functional capacity; (8) Echocardiography; (9) Electrocardiography; and (10) Cardiopulmonary hemodynamics on RHC. On echocardiography, we specifically determined whether there was evidence of left‐sided (i.e., mild or greater aortic regurgitation/stenosis; mild or greater mitral regurgitation/stenosis; LV ejection fraction ≤ 40%; left atrial dilation) or right‐sided (i.e., mild or greater tricuspid regurgitation, mild or greater pulmonic regurgitation; right atrial dilation; right ventricular [RV] dilation and/or systolic dysfunction) cardiac structural abnormalities based on chart extraction. Additionally, we identified patients who underwent cardiac imaging including either cardiac magnetic resonance imaging or positron emission tomography. The primary outcome was a composite of lung transplantation and all‐cause mortality from the time of RHC. Patients were followed until an end‐date of January 1, 2023, to ensure ≥ 3 years of follow‐up. We used multiple imputation by chained equations to replace missing data. Cox proportional hazard regression models were employed to determine whether QRS interval was associated with an age‐ and sex‐adjusted composite outcome of lung transplantation and all‐cause mortality. Patients who did not reach the primary outcome were censored at the last clinic/hospital visit or at the end of the study period, whichever occurring first. Covariables were evaluated for proportional hazards assumption using Schoenfeld residuals. A sensitivity analysis was performed excluding patients lost to follow‐up to determine whether this was informative about mortality. Lastly, we performed a comparison using the same Cox proportional hazards model replacing QRS interval with widely known mortality predictors, brain natriuretic peptide (BNP) and 6‐min walking distance (6MWD) and compared each effect estimate. The cutoffs for BNP and 6MWD were 200 pg/mL and 165 meters, based on the REVEAL 2.0 score [8]. R version 4.3.0 (R Foundation for Statistical Computing, Vienna, Austria) was used with “mice” and “survival” packages.
3. Results
After excluding six patients with paced rhythms, there were 68 with SaPH; 32 (47.1%) had pre‐capillary PH, 15 (22.1%) had isolated post‐capillary PH, and 9 (13.2%) had combined pre‐ and post‐capillary PH. Of the 13 (19.1%) patients with imaging suggestive of cardiac sarcoidosis, 4 (30.8%) demonstrated an LV ejection fraction ≤ 40%. Patient clinical characteristics are summarized in Table 1. There were 18 (26.5%) who did not have a recorded ECG at the time of RHC. Median time interval between ECG and RHC was 0 (IQR: 0, 0.1) months. On ECG, 14 (20.6%) had QRS prolongation, most commonly due to right bundle branch block (RBBB) in 10 (71.4%) patients. There were 2 (14.3%) patients with left bundle branch block (LBBB), and 2 (14.3%) patients with intraventricular conduction delay. Patients with and without QRS prolongation exhibited similar cardiopulmonary hemodynamics. However, patients with QRS prolongation had higher brain natriuretic peptide levels and more limited functional capacity by New York Heart Association (NYHA) classification. On echocardiography, these patients had an increased proportion of left‐ and right‐sided structural abnormalities. In the entire cohort, there were 18 (23.5%) who died, 1 (1.5%) who underwent lung transplantation, and 18 (23.5%) who were lost to follow‐up. The 1‐year and 3‐year percentages of patients who died or underwent lung transplantation were 8.0% and 26.0%, respectively. Of the 19 patients who met the primary outcome, most had pre‐capillary PH (n = 10) followed by isolated post‐capillary PH (n = 6). Every 10‐ms increase in QRS interval was associated with an age‐ and sex‐adjusted HR of 1.23 (95% CI: 1.06, 1.44) for the composite outcome of lung transplantation and all‐cause mortality. A sensitivity analysis resulted in an adjusted HR of 1.19 (95% CI: 1.02, 1.39). Because there were missing data for BNP in 3 (4.4%) patients and 6MWD in 23 (33.8%) patients, these values were imputed and hence excluded from the analysis, resulting in 43 patients (with 9 deaths). Within this study cohort, each 10 ms increase in QRS duration yielded an adjusted HR of 1.37 (95% CI: 1.11, 1.69; p = 0.004) for each 10 ms increase in QRS for all‐cause mortality. When we replaced QRS duration with a BNP of ≥ 200 pg/mL, it yielded an adjusted HR of 1.58 (95% CI: 0.37, 6.85). When we replaced QRS duration with a 6MWD < 165 m, it yielded an adjusted HR of 3.54 (95% CI: 0.57, 21.84).
Table 1.
Clinical characteristics associated with QRS prolongation on electrocardiography.
| QRS interval < 120 ms (n = 54) | QRS interval ≥ 120 ms (n = 14) | |
|---|---|---|
| Demographics | ||
| Age at PH diagnosis, years (mean ± SD) | 60.9 ± 10.9 | 59.1 ± 13.2 |
| Sex, male, n (%) | 28 (51.9%) | 9 (64.3%) |
| Body mass index, kg/m2 (mean ± SD) | 32.6 ± 7.9 | 34.8 ± 12.3 |
| Current/former tobacco use history, n (%) | 32 (59.3%) | 6 (42.9%) |
| Cardiac sarcoidosis on FDG‐PET and/or CMR, n (%) | 10 (18.5%) | 3 (21.4%) |
| Pulmonary hypertension classification | ||
| Pre‐capillary PHa, n (%) | 25 (46.3%) | 7 (50.0%) |
| Isolated post‐capillary PHb, n (%) | 11 (20.4%) | 4 (28.6%) |
| Combined pre‐ and post‐capillary PHc, n (%) | 7 (13.0%) | 2 (14.3%) |
| Comorbid conditions | ||
| Coronary artery disease, n (%) | 11 (20.4%) | 5 (35.7%) |
| Atrial fibrillation/atrial flutter, n (%) | 6 (11.1%) | 2 (14.3%) |
| Diabetes mellitus, n (%) | 23 (42.6%) | 4 (28.6%) |
| Hypertension, n (%) | 35 (64.8%) | 7 (50.0%) |
| Hyperlipidemia, n (%) | 22 (40.7%) | 4 (28.6%) |
| Venous thromboembolism, n (%) | 11 (20.4%) | 2 (14.3%) |
| Obstructive sleep apnea, n (%) | 18 (33.3%) | 5 (35.7%) |
| Sarcoidosis stage | ||
| Stage 1, n (%) | 11 (20.4%) | 2 (14.3%) |
| Stage 2, n (%) | 9 (16.7%) | 2 (14.3%) |
| Stage 3, n (%) | 3 (5.6%) | 1 (7.1%) |
| Stage 4, n (%) | 21 (38.9%) | 7 (50.0%) |
| Pulmonary function testing | ||
| FVC, % predicted (mean ± SD) | 74.7 ± 17.4 | 73.2 ± 24.7 |
| FEV1, % predicted (mean ± SD) | 67.3 ± 19.9 | 69.1 ± 25.3 |
| FEV1/FVC, % (mean ± SD) | 72.6 ± 12.8 | 74.2 ± 10.6 |
| TLC, % predicted (mean ± SD) | 73.5 ± 17.5 | 76.3 ± 17.3 |
| DLCO, % predicted (mean ± SD) | 51.8 ± 20.2 | 56.1 ± 16.9 |
| Brain natriuretic peptide levels | ||
| BNP 50 to < 200 pg/mL, n (%) | 15 (27.8%) | 5 (35.7%) |
| BNP 200 to < 800 pg/mL, n (%) | 8 (14.8%) | 3 (21.4%) |
| BNP ≥ 800 pg/mL, n (%) | 5 (9.3%) | 4 (28.6%) |
| Functional capacity | ||
| 6MWD, m (mean ± SD) | 300.6 ± 117.8 | 276.2 ± 82.1 |
| NYHA Class 3/4 functional classification, n (%) | 30 (55.6%) | 11 (78.6%) |
| Echocardiography | ||
| Aortic regurgitation, n (%) | 5 (9.3%) | 2 (14.3%) |
| Mitral regurgitation, n (%) | 11 (20.4%) | 4 (28.6%) |
| Tricuspid regurgitation, n (%) | 26 (48.1%) | 6 (42.9%) |
| Pulmonic regurgitation, n (%) | 6 (11.1%) | 3 (21.4%) |
| Aortic stenosis, n (%) | 5 (9.3%) | 2 (14.3%) |
| Mitral stenosis, n (%) | 3 (5.6%) | 2 (14.3%) |
| LVEF, % (mean ± SD) | 60.1 ± 11.1 | 45.8 ± 17.7 |
| LVEF ≤ 40%, n (%) | 4 (7.4%) | 6 (42.9%) |
| LA dilation, n (%) | 13 (24.1%) | 6 (42.9%) |
| RA dilation, n (%) | 15 (27.8%) | 6 (42.9%) |
| RV dilation, n (%) | 17 (31.5%) | 7 (50.0%) |
| RV systolic dysfunction, n (%) | 10 (18.5%) | 7 (50.0%) |
| Pericardial effusion, n (%) | 17 (31.5%) | 2 (14.3%) |
| Electrocardiography | ||
| Ventricular rate, bpm (mean ± SD) | 76.1 ± 15.6 | 76.6 ± 12.6 |
| P‐axis, degrees (mean ± SD) | 48.6 ± 18.1 | 47.4 ± 22.7 |
| R‐axis, degrees (mean ± SD) | 30.4 ± 46.1 | 17.1 ± 78.5 |
| T‐axis, degrees (mean ± SD) | 41.9 ± 47.0 | 40.7 ± 72.7 |
| Right axis deviationd, n (%) | 5 (9.3%) | 5 (35.7%) |
| Left axis deviatione, n (%) | 4 (7.4%) | 5 (35.7%) |
| PR interval, ms (mean ± SD) | 161.3 ± 24.5 | 178.3 ± 18.3 |
| PR prolongationf, n (%) | 3 (5.6%) | 2 (14.3%) |
| QTc interval, ms (mean ± SD) | 445.3 ± 27.5 | 497.5 ± 35.2 |
| QTc prolongationg, n (%) | 2 (3.7%) | 7 (50.0%) |
| Cardiopulmonary hemodynamics | ||
| RAP, mm Hg (mean ± SD) | 6.8 ± 4.7 | 9.0 ± 6.4 |
| mPAP, mm Hg (mean ± SD) | 32.6 ± 8.3 | 33.9 ± 8.2 |
| PAWP, mm Hg (mean ± SD) | 13.3 ± 5.9 | 15.1 ± 7.7 |
| PVR, wood units (mean ± SD) | 4.1 ± 2.5 | 4.2 ± 2.1 |
| CI, L/min/m2 (mean ± SD) | 2.6 ± 0.6 | 2.4 ± 0.6 |
Abbreviations: 6MWD, 6‐min walk distance; BNP, brain natriuretic peptide; CI, cardiac index; CMR, cardiac magnetic resonance imaging; DLCO, diffusing capacity for carbon monoxide; FDG‐PET, fludeoxyglucose‐positron emission tomography; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; LA, left atrial; LV, left ventricular; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary artery pressure; NYHA, New York Heart Association; PAWP, pulmonary arterial wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RA, right atrial; RAP, right atrial pressure; RV, right ventricular; TLC, total lung capacity.
Pre‐capillary PH: mPAP > 20 mm Hg, PAWP ≤ 15 mm Hg, PVR ≥ 3 Wood Units.
Isolated Post‐capillary PH: mPAP > 20 mm Hg, PAWP > 15 mm Hg, PVR < 3 Wood Units.
Combined Pre‐ and Post‐capillary PH: mPAP > 20 mm Hg, PAWP > 15 mm Hg, PVR ≥ 3 Wood Units.
Right Axis Deviation: R‐axis between +90° and +180°.
Left Axis Deviation: R‐axis between −30° and +90°.
PR Prolongation: PR interval > 200 ms.
QTc Prolongation: QTc interval > 500 ms.
4. Discussion
SaPH is a heterogeneous, multifactorial disease. Herein, we investigated the contribution of cardiac conduction abnormalities via ECG for risk‐stratifying patients with SaPH. We demonstrated that QRS prolongation was associated with increased HR for our composite outcome of lung transplantation and all‐cause mortality. QRS prolongation, predominantly RBBB, was the most commonly observed cardiac conduction abnormality, likely reflective of RV dyssynchrony [9]. In idiopathic pulmonary arterial hypertension (PAH), QRS prolongation occurred in 16.5%, predominantly RBBB, and was associated with worse functional capacity and all‐cause mortality [10], similar to that observed in the present study. Interestingly, there was a marginally increased proportion of patients with QRS prolongation in those with sarcoidosis (20.6%) in the present study compared to a prior with idiopathic PAH [10], which appeared to be driven by the presence of LBBB, absent in the latter. The occurrence of LBBB suggests that overlap between cardiac sarcoidosis and SaPH may exist. Moreover, while those with and without QRS prolongation had similar cardiopulmonary hemodynamics and PH classification, patients with QRS prolongation had more advanced symptoms (NYHA Class III/IV) and a greater proportion of reduced LV ejection fraction that may reflect the presence of cardiomyopathy. Based on the echocardiography and ECG data in the current study, LV dysfunction may be more common in SaPH than previously recognized.
There were limitations to the study. Because it was observational, there may be disparities in data availability and timing. There were 18 (23.5%) patients who did not have an ECG at the time of RHC for unclear reasons. This may indicate that the procedure was performed in the intensive care setting and possibly greater severity of PH. This could certainly be a source of selection bias. Our comparative analysis with known risk factors of mortality in PH, BNP, and 6MWD, was limited due to the degree of missing data. Nonetheless, to mitigate this, we imputed missing data. While 18 (23.5%) patients were lost to follow‐up, a sensitivity analysis was compatible with our primary results. It is possible that excluding patients who underwent pacemaker implantation may lead to selection bias due to underestimation of the true proportion with QRS prolongation. However, this was unavoidable due to the timing of PH diagnosis by RHC. Unfortunately, there were no patients who underwent endomyocardial biopsy to confirm cardiac involvement of sarcoidosis in our cohort. Lastly, the study time interval also coincided with redefining of PH (mPAP > 20 mmHg), which may have impacted our findings [7]. It will be imperative to verify our results in a prospective, multicenter manner.
In conclusion, QRS prolongation was a commonly observed cardiac conduction abnormality in SaPH which may be reflective of concurrent cardiac sarcoidosis, RV enlargement from high afterload in the setting of PH, or other concurrent cardiovascular disease. Nonetheless, QRS prolongation was associated with poor clinical outcomes in patients with SaPH. Our findings reinforce the significant clinical role for ECG, a noninvasive test that is widely available, low‐cost and commonly used in screening for cardiac involvement may also be helpful for risk‐stratifying patients with SaPH. Future prospective studies may provide further granular data on cardiovascular workup as well as further delineating the reason for increased mortality among patients with SaPH and QRS prolongation.
Author Contributions
Juan V. Rodriguez made substantial contributions to the acquisition of data, drafted the article, and revised it critically for important intellectual content. Haihua Zhang made substantial contributions to the acquisition of data, drafted the article, and revised it critically for important intellectual content. Nathan Mesfin made substantial contributions to the acquisition of data, interpretation of the data, and revised the article critically for important intellectual content. Elizabeth S. Klings made substantial contributions to study conception, design, analysis, and interpretation, and revised the article critically for important intellectual content. Justin K. Lui made substantial contributions to study conception, design, acquisition of data, analysis, and interpretation of data, and revised the article critically for important intellectual content. All authors gave final approval of the version of the article.
Ethics Statement
The study was approved by the Institutional Review Board at Boston University Medical Campus.
Conflicts of Interest
Elizabeth S. Klings receives research support from Novartis, Novo Nordisk, and United Therapeutics. Elizabeth S. Klings has served as a consultant/advisory board member for Novo Nordisk, Vertex, Pfizer, and CSL Behring for sickle cell disease‐related clinical trials (no conflict with the present work). Elizabeth S. Klings received royalties for three topic cards in UpToDate. Justin K. Lui has previously received research support from United Therapeutics within the past 3 years.
Acknowledgments
Nathan Mesfin is supported jointly by the University of Minnesota Medical School and Clinical and Translational Science Institute (CTSI) at the University of Minnesota. Elizabeth S. Klings is supported by the National Institute of Health/National Heart, Lung, and Blood Institute (1UG3 HL143192), National Center for Advancing Translational Sciences (2UL1TR001430), and Health Resources and Services Administration (U1EMC27864‐08‐00) and receives research support from Novo Nordisk, Novartis, and United Therapeutics. Justin K. Lui is supported by the National Scleroderma Foundation and the American Heart Association grant 23CDA1052352.
This study's contents are solely the responsibility of the authors and do not necessarily reflect the official views of the NIH or any of the funding organizations. Justin K. Lui accepts official responsibility for the overall integrity of this work.
Juan V. Rodriguez and Haihua Zhang contributed equally to this article.
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